There is a significant need for novel HIV therapies given the emergence of viruses resistant to existing drug regimens. The Rev-RRE protein-RNA interaction in HIV plays an essential role in the transport of viral mRNA from the nucleus to the cytoplasm where it can be translated or packaged. Previously we identified the thienopyridine scaffold that inhibited HIV replication and by targeting HIV Rev. We carried out extensive structure-activity (SAR) studies producing patentable new analogs that are 100-fold more potent than our original screening hits and with therapeutic indices >10,000, exceeding our original goals. Having successfully completed key milestones towards submission of an Investigational New Drug (IND), we propose to carry out a detailed study of the mechanism of action of the inhibitors. This study is a key scientific milestone that will open many corporate and venture opportunities, as well as significantly strengthen our opportunity to access SBIR/STTR Phase II funding. The work described in this proposal has a high likelihood for success given that in preliminary studies we have shown that a mutant in the RRE confers resistance to the compound.